: The objective of this study is to elucidate the factors that limit maximal 02 consumption (V02max) and performance in working skeletal muscle. 1) The hypothesis that V02 max can be limited by the capacity for 02 diffusion in the peripheral tissue will be tested using an isolated, in situ canine gastrocnemius model, and the isolated knee extensor muscle model in humans. A mathematical model incorporating diffusion limitation has been developed from a combination of Fick's law of diffusion and the Fick principle. A. This model will be used to predict the outcome of various experiments in which 02 delivery is altered through lowered arterial P02, anemia, and ischemia. Special experiments in which the )2 delivery (muscle blood flow X arterial 02 content) will be kept equal between varied conditions of hypoxemia, anemia, and muscle blood flow will be used in both the animal and human studies in an attempt to separate perfusion limitation from diffusion limitation. B. Because muscle blood flow to V02 heterogeneity can mimic 02 diffusion limitation, the problem of tissue heterogeneity will also be investigated in the canine gastrocnemius model using step changes in inert gas and 02 levels of arterial blood and following the muscle venous responses, using methodology developed investigating for pulmonary heterogeneity. 2) Several factors that determine muscle function and performance during high-intensity work will also be investigated. A. The NAD redox state during progressive work will be measured to determine tissue oxygenation and its control of metabolism. B. The role of glycolysis during intense work and the impact of increased activation-relaxation cycles on contractile function and fatigue will be investigated. These experiments will also provide information concerning the amount of ATP produced by glycolysis that is used for membrane functions. C. In all of the experiments in which 02 delivery is manipulated, the development of fatigue will be studied along with changes in blood and muscle acid-base balance. D) Finally, the potential role of granulocyte plugging of muscle microcirculatin after surgery in reducing in situ maximal blood flow will also be investigated.